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. 2021 Jul 6;16(1):301.
doi: 10.1186/s13023-021-01917-y.

Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)

Matthias Sauter  1 , Elena Belousova  2 , Mirjana P Benedik  3 , Tom Carter  4 , Vincent Cottin  5 , Paolo Curatolo  6 , Maria Dahlin  7 , Lisa D'Amato  8 , Guillaume B d'Augères  9 , Petrus J de Vries  10 , José C Ferreira  11 , Martha Feucht  12 , Carla Fladrowski  13   14 , Christoph Hertzberg  15 , Sergiusz Jozwiak  16   17 , John A Lawson  18 , Alfons Macaya  19 , Ruben Marques  8   20 , Rima Nabbout  21 , Finbar O'Callaghan  22 , Jiong Qin  23 , Valentin Sander  24 , Seema Shah  25 , Yukitoshi Takahashi  26 , Renaud Touraine  27 , Sotiris Youroukos  28 , Bernard Zonnenberg  29 , Anna Jansen  30 , J Chris Kingswood  31 ; TOSCA investigators
Collaborators, Affiliations

Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)

Matthias Sauter et al. Orphanet J Rare Dis. .

Abstract

Background: Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients.

Methods: TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2).

Results: Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%).

Conclusion: Rare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.

Keywords: Malignancy; Rare manifestation; TOSCA; TSC; Tuberous sclerosis complex.

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Conflict of interest statement

MS, EB, TC, VC, PC, GBd’A, JCK, JCF, MF, CF, CH, SJ, RN, FO’C, JQ, RT, MD, JAL, AM, SY, MPB, ACJ, PJdV, and BZ received honoraria and support for travel from Novartis. VC received personal fees for consulting, lecture fees and travel from Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, MSD, Novartis, Pfizer, Roche, Sanofi; grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, Roche; personal fees for developing educational material from Boehringer Ingelheim and Roche. PJdV has been on the study steering group of the EXIST-1, 2 and 3 studies sponsored by Novartis, and co-PI on two investigator-initiated studies part-funded by Novartis. RN received grant support, paid to her institution, from Eisai and lectures fees from Nutricia, Eisai, Advicenne and GW Pharma. YT received personal fees from Novartis for lecture and for copyright of referential figures from the journals and received a grant from the Japanese government for intractable epilepsy research. SJ was partly financed by the EC Seventh Framework Programme (FP7/2007-2013; EPISTOP, grant agreement no. 602391), the Polish Ministerial funds for science (years 2013-2018) for the implementation of international co-financed project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016. JCK, PC, CH, JAL, and JQ received a research grant from Novartis. RM, LD’A and SS are employees of Novartis. VS and SV reported no conflict of interest. This study was funded by Novartis Pharma AG. All authors approved the final version of the manuscript prior to submission.

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